International Journal of

Molecular Sciences Review

Histone Lysine Methylation and Neurodevelopmental Disorders Jeong-Hoon Kim 1,2,† , Jang Ho Lee 3,† Kyoung Sang Cho 3, * 1 2 3 4

* †

, Im-Soon Lee 3 , Sung Bae Lee 4, * and

Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea; [email protected] Department of Functional Genomics, University of Science and Technology, Daejeon 34113, Korea Department of Biological Sciences, Konkuk University, Seoul 05029, Korea; [email protected] (J.H.L.); [email protected] (I.-S.L.) Department of Brain & Cognitive Sciences, DGIST, Daegu 42988, Korea Correspondence: [email protected] (S.B.L.); [email protected] (K.S.C.); Tel.: + 82-53-785-6122 (S.B.L.); +82-2-450-3424 (K.S.C.) These authors contributed equally to this work.

Received: 13 June 2017; Accepted: 27 June 2017; Published: 30 June 2017

Abstract: Methylation of several lysine residues of histones is a crucial mechanism for relatively long-term regulation of genomic activity. Recent molecular biological studies have demonstrated that the function of histone methylation is more diverse and complex than previously thought. Moreover, studies using newly available genomics techniques, such as exome sequencing, have identified an increasing number of histone lysine methylation-related genes as intellectual disability-associated genes, which highlights the importance of accurate control of histone methylation during neurogenesis. However, given the functional diversity and complexity of histone methylation within the cell, the study of the molecular basis of histone methylation-related neurodevelopmental disorders is currently still in its infancy. Here, we review the latest studies that revealed the pathological implications of alterations in histone methylation status in the context of various neurodevelopmental disorders and propose possible therapeutic application of epigenetic compounds regulating histone methylation status for the treatment of these diseases. Keywords: epigenetic changes; histone lysine methylation; lysine methyltransferase; lysine demethylase; neurodevelopmental disorder

1. Introduction Post-translational modifications of histone proteins in eukaryotic cells serve as crucial regulatory mechanisms of gene expression and are important for maintaining genomic integrity [1,2]. The histone modifications, such as its acetylation, methylation, phosphorylation, and ubiquitination, influence genomic activity by altering the binding force of DNA to histones or by acting as marks that recruit specific histone binding proteins [2]. Among these histone modifications, methylation has been implicated in heterochromatin formation and the regulation of promoter activity [3,4]. The histone residues, on which methylation occurs, include the following lysine and arginine residues: H3 (K4, 9, 27, 36, and 79), H4K20, H3 (R2, 8, 17, and 26), and H4R3 [5,6] (Figure 1a). These methylation sites are evolutionarily well conserved [7]. A variety of histone methyltransferases (writers), histone demethylases (erasers), and methylated histone binding proteins (readers) have been identified in various eukaryotic genomes [8]. Their site-specific molecular functions have been defined by biochemical and genetic studies [2,8] (Table 1).

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of epigenetic modifications are associated with various human diseases, including Int. J. Dysregulation Mol. Sci. 2017, 18, 1404 2 of 20 neurodevelopmental disorders [9,10]. In particular, an increasing number of mutations in histone lysine histone lysine methylation-related have as been identified as intellectual disability-associated methylation-related genes have beengenes identified intellectual disability-associated genes by exome genes by exome with patients’ samples1b [11–14] (Figure and Table 2). the Thisimportance highlights sequencing with sequencing patients’ samples [11–14] (Figure and Table 2). 1b This highlights theproper importance of of proper control of histone methylation during neurogenesis. the current article, of control histone methylation during neurogenesis. In the currentInarticle, we provide we overview provide anofoverview the lateston updates on the pathological implication of alterations in histone an the latestofupdates the pathological implication of alterations in histone lysine lysine methylation in terms of neurodevelopmental disorders. Through weto trypredict to predict methylation status status in terms of neurodevelopmental disorders. Through this, this, we try the the future direction of research on this emerging future direction of research on this emerging field.field.

Figure 1. Histone methylation and neurodevelopmental disorders: (a) histone methylation sites in the Figure 1. Histone methylation and neurodevelopmental disorders: (a) histone methylation sites in the tails of histone H3 and H4; and (b) histone methyltransferases, demethylases, and methylated histone tails of histone H3 and H4; and (b) histone methyltransferases, demethylases, and methylated histone binding proteins linked with neurodevelopmental disorders. Five methylation sites were associated binding proteins linked with neurodevelopmental disorders. Five methylation sites were associated with several neurodevelopmental disorders. BWS, Beckwith-Wiedemann syndrome; KABUK1/2, with several neurodevelopmental disorders. BWS, Beckwith-Wiedemann syndrome; KABUK1/2, Kabuki syndrome 1/2; KBGS, KBG syndrome; KS, Kleefstra syndrome; MGORS1, Meier-Gorlin Kabuki syndrome 1/2; KBGS, KBG syndrome; KS, Kleefstra syndrome; MGORS1, Meier-Gorlin syndrome 1; MRXSCJ, Mental retardation, X-linked, syndromic, Claes-Jensen type; MRXSSD, Siderius syndrome 1; MRXSCJ, Mental retardation, X-linked, syndromic, Claes-Jensen type; MRXSSD, Siderius X-linked mental retardation syndrome; PSS, Potocki-Shaffer syndrome; SCZD, Schizophrenia; X-linked mental retardation syndrome; PSS, Potocki-Shaffer syndrome; SCZD, Schizophrenia; SOTOS1, SOTOS1, Sotos syndrome 1; WDSTS, Wiedemann-Steiner syndrome; WHS, Wolf-Hirshhorn Sotos syndrome 1; WDSTS, Wiedemann-Steiner syndrome; WHS, Wolf-Hirshhorn syndrome; WVS, syndrome; WVS, Weaver syndrome. Weaver syndrome.

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Table 1. The names of the histone methylation-related factors mentioned in this paper and their synonyms. Symbol

Previous Symbol

Synonym(s)

Residue

Function

ASH1L DOT1L EHMT1 EHMT2 EZH1 EZH2 KDM1A

ASH1L DOT1L EHMT1 BAT8, C6orf30 EZH1 EZH2 AOF2, KDM1

H3K36 H3K79 H3K9 H3K9 H3K27 H3K27 H3K4, H3K9, H4K20

Methyltransferase Methyltransferase Methyltransferase Methyltransferase Methyltransferase Methyltransferase Demethylase

KDM2A

FBXL11, KDM2A

H3K36

Demethylase

KDM2B KDM3A KDM3B KDM4A KDM4B KDM4C KDM5A

FBXL10, KDM2B JMJD1, JMJD1A, KDM3A C5orf7, JMJD1B, KDM3B JMJD2, JMJD2A, KDM4A JMJD2B, KDM4B JMJD2C, KDM4C JARID1A, KDM5A, RBBP2 JARID1C, KDM5C, MRX13, SMCX KDM6A, UTX JMJD3, KDM6B KMT2A, MLL KMT2B KMT2C, MLL3 KMT2D, MLL2, TNRC21 KMT5A, SETD8 KMT5B, SUV420H1 KMT5C, SUV420H2 STO WHSC1 WHSC1L1

ASH1, ASH1L1, huASH1, KMT2H DOT1, KIAA1814, KMT4 bA188C12.1, Eu-HMTase1, FLJ12879, KIAA1876, KMT1D Em:AF134726.3, G9A, KMT1C, NG36/G9a KIAA0388, KMT6B ENX-1, EZH1, KMT6, KMT6A BHC110, KIAA0601, LSD1 CXXC8, DKFZP434M1735, FBL11, FBL7, FLJ00115, JHDM1A, KIAA1004, LILINA CXXC2, Fbl10, JHDM1B, PCCX2 JHMD2A, KIAA0742, TSGA KIAA1082, NET22 JHDM3A, KIAA0677, TDRD14A KIAA0876, TDRD14B GASC1, KIAA0780, TDRD14C -

H3K36 H3K9 H3K9 H3K9, H3K36 H3K9, H3K36 H3K9, H3K36 H3K4

Demethylase Demethylase Demethylase Demethylase Demethylase Demethylase Demethylase

KDM5C KDM6A KDM6B KMT2A KMT2B KMT2C KMT2D KMT5A KMT5B KMT5C NSD1 NSD2 NSD3

DXS1272E, XE169

H3K4

Demethylase

KIAA0346 ALL-1, CXXC7, HRX, HTRX1, MLL1A, TRX1 CXXC10, HRX2, KIAA0304, MLL1B, MLL2, MLL4, TRX2, WBP7 HALR, KIAA1506 ALR, CAGL114, MLL4 PR-Set7, SET07, SET8 CGI-85 MGC2705 ARA267, FLJ22263, KMT3B KMT3G, MMSET FLJ20353, KMT3F, WHISTLE

H3K27 H3K27 H3K4 H3K4 H3K4 H3K4 H4K20 H4K20 H4K20 H3K36 H3K36 H3K36

Demethylase Demethylase Methyltransferase Methyltransferase Methyltransferase Methyltransferase Methyltransferase Methyltransferase Methyltransferase Methyltransferase Methyltransferase Methyltransferase

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Table 1. Cont. Symbol ORC1 PHF2 PHF8 PHF21A RIOX1 SETD1A SETD1B SETD2 SETD3 SETDB1 SETMAR SMYD2 SUV39H1 SUV39H2 UTY

Previous Symbol

Synonym(s)

Residue

ORC1L HSORC1, PARC1 H4K20 CENP-35, JHDM1E, KDM7C, KIAA0662 H3K9, H4K20 JHDM1F, KDM7B, KIAA1111, ZNF422 H3K9, H4K20/H3K4 BHC80, BM-006, KIAA1696 H3K4 C14orf169 FLJ21802, JMJD9, MAPJD, NO66 H3K4, H3K36 KIAA0339, KMT2F, Set1 H3K4 KIAA1076, KMT2G, Set1B H3K4 FLJ23184, HIF-1, HYPB, KIAA1732, KMT3A H3K36 C14orf154 FLJ23027 H3K4, H3K36 SETDB1 ESET, KG1T, KIAA0067, KMT1E, TDRD21 H3K9 Mentase H3K4, H3K36 HSKM-B, KMT3C, ZMYND14 H3K4, H3K36 SUV39H KMT1A H3K9 SUV39H2 KMT1B FLJ23414 H3K9 UTY KDM6AL, KDM6C H3K27 The names of the proteins are followed by HUGO Gene Nomenclature Committee (http://www.genenames.org/)

Function Recognition Demethylase Demethylase/Recognition Recognition Demethylase Methyltransferase Methyltransferase Methyltransferase Methyltransferase Methyltransferase Methyltransferase Methyltransferase Methyltransferase Methyltransferase Demethylase

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Table 2. Neurodevelopmental disorders caused by mutations in histone methylation-related genes. Disorder

OMIM

Symptom

Gene

Residue

Function

Beckwith-Wiedemann syndrome (BWS)

130650

Pediatric overgrowth disorder involving a predisposition to tumor development

NSD1

H3K36

Methyltransferase

Kabuki syndrome 1

147920

H3K4 H3K27

Methyltransferase Demethylase

300867

Congenital mental retardation, postnatal dwarfism, peculiar faces, broad and depressed nasal tip, large prominent earlobes, cleft or high-arched palate, scoliosis, short fifth finger, and persistence of finger pads

KMT2D KDM6A

Kabuki syndrome 2 (KABUK1/2) KBG syndrome (KBGS)

148050

Macrodontia of the upper central incisors, distinctive craniofacial findings, short stature, skeletal anomalies, neurologic involvement that includes global developmental delay, seizures, and intellectual disability

KDM1A

H3K4 H3K9 H4K20

Demethylase Demethylase Demethylase

Kleefstra syndrome (KS)

610253

Severe mental retardation, hypotonia, epileptic seizures, flat face with hypertelorism, synophrys, anteverted nares, everted lower lip, carp mouth with macroglossia, and heart defects

KMT2B, KMT2C EHMT1

H3K4 H3K4 H3K9

Methyltransferase Methyltransferase Methyltransferase

Meier-Gorlin syndrome 1 (MGORS1)

224690

Severe intrauterine and postnatal growth retardation, microcephaly, bilateral microtia, and aplasia or hypoplasia of the patellae

ORC1

H4K20

Recognition

Mental retardation, X-linked, syndromic, Claes-Jensen type (MRXSCJ)

300534

Severe mental retardation, slowly progressive spastic paraplegia, facial hypotonia, and maxillary hypoplasia

KDM5C

H3K4

Demethylase

Potocki-Shaffer syndrome (PSS)

601224

Craniofacial abnormalities, developmental delay, intellectual disability, multiple exostoses, and biparietal foramina

PHF21A

H3K4

Recognition

Schizophrenia (SCZD)

181500

Hallucinations and delusions, severely inappropriate emotional responses, disordered thinking and concentration, erratic behavior, as well as social and occupational deterioration

SETD1A

H3K4

Methyltransferase

Siderius X-linked mental retardation syndrome (MRXSSD)

300263

Mental retardation, a repaired cleft lip, a long face with broad nasal tip, long hands with long thin fingers, and flat feet with long thin toes

PHF8

H3K4 H3K9 H4K20

Recognition Demethylase Demethylase

Sotos syndrome 1 (SOTOS1)

117550

Excessively rapid growth, acromegalic features, and non-progressive cerebral disorder with mental retardation

NSD1

H3K36

Methyltransferase

Weaver syndrome (WVS)

277590

Pre- and postnatal overgrowth, accelerated osseous maturation, characteristic craniofacial appearance, and developmental delay, broad forehead and face, ocular hypertelorism, prominent wide philtrum, micrognathia, deep horizontal chin groove, and deep-set nails

EZH2

H3K27

Methyltransferase

Wiedemann-Steiner syndrome (WDSTS)

605130

Hypertrichosis cubiti associated with short stature, consistent facial features, including long eyelashes, thick or arched eyebrows with a lateral flare, down slanting and vertically narrow palpebral fissures, mild to moderate intellectual disability, behavioral difficulties, and hypertrichosis on the back

KMT2A

H3K4

Methyltransferase

Wolf-Hirschhorn syndrome (WHS)

194190

Pre- and postnatal growth deficiency, developmental disability of variable degree, characteristic craniofacial features, and a seizure disorder

NSD2

H3K36

Methyltransferase

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2. Histone Lysine Methylations and Related Factors In most cases, methylation of histone H3 lysine 4 (H3K4me) is primarily found at enhancers and promoters of actively transcribed genes, and the methylation status of genes (i.e., mono-, di-, tri-methylation) correlates with its transcriptional activity [15,16]. Members of the lysine methyl transferase 2 (KMT2) family catalyze the addition of methyl groups to H3K4 at the post-translational level, while lysine demethylases (KDMs) remove the methyl groups. This dynamically modulates chromatin structures [17,18]. The KMT2 family, which is highly conserved throughout eukaryotes, can be evolutionarily divided into three subgroups (i.e., KMT2A and KMT2B, KMT2C and KMT2D, and SETD1A and SETD1B) [4,19]. In addition, SMYD2 and SETD3 also have been identified as H3K4 methyltransferases, and eight KDMs are reported to target the H3K4me [4,20]. Methylation of histone H3 lysine 9 (H3K9me) is associated with both heterochromatin formation and gene silencing in euchromatin [2]. H3K9me acts as a binding sit Counseling, e for HP1 [21,22] which forms a complex with chromatin-modifying factors crucial for heterochromatin formation when recruited to H3K9me [23,24]. In the euchromatic region, H3K9me contributes to HP1-mediated gene silencing [25]. H3K9me is catalyzed by several methyltransferases, such as EHMT1, EHMT2, SUV39H1, SUV39H2, SETDB1, dimeric EHMT1-EHMT2, and the PRDM family, and erased by the following lysine demethylases: KDM1, KDM3, KDM4, PHF2, and PHF8 [8,26,27]. Histone H3 lysine 27 methylation (H3K27me) is a repressive chromatin mark that is involved in gene silencing during development and X-chromosome inactivation [28,29]. H3K27me is associated with the repression of developmental regulator genes in human and murine embryonic stem cells (ESCs) [30,31]. Intriguingly, a variety of promoters characteristically contain both H3K4me3 (an activating mark) and H3K27me (a repressive mark) in pluripotent ESCs, which is referred to as “bivalency.” The change in the bivalent situation is associated with differentiation [32]. H3K27me, catalyzed by EZH1 or EZH2 containing Polycomb Repressive Complex (PRC) 2, is a binding site for PRC1 to compact chromosomes [33]. KDM6A, KDM6B, and UTY have been identified as erasers of H3K27me [8]. A role of methylation on histone H3 lysine 36 (H3K36me) has initially been reported in the activation of genes in various systems [34]. However, H3K36me also functions in various processes, including alternative splicing [35], dosage compensation [36], DNA damage response [37], and transcriptional repression [38], depending on the chromatin context. H3K36me is tightly regulated by multiple KMTs and KDMs [20]. In vitro and in vivo studies, to date, have demonstrated that there are the following eight types of KMTs regulating H3K36 methylation levels in humans: SETD2, SETD3, NSD1, NSD2, NSD3, ASH1L, SMYD2, and SETMAR [20]. Although all H3K36-specific methyltransferases contain highly conserved SET domains, the patterns of H3K36 methylation vary. Most H3K36 KMTs preferentially mono- and di-methylate the residue, whereas SETD2 is the only enzyme that catalyzes H3K36me3 and requires mono- or di-methylated H3K36 for its function [39]. Conversely, methylated H3K36 can be demethylated by six KDMs. The H3K36 KDMs, which all belong to the Jumonji protein family, contain the conserved JmjC domain consisting of the following three groups: JHDM1 (KDM2A, KDM2B), JHDM3 (KDM4A, KDM4B, KDM4C), and RIOX1 [40]. JHDM1 is specific for H3K36me1/me2 demethylation, whereas JHDM3 uses H3K36 and H3K9 residues as substrates for the me2/me3-specific demethylation [41]. Similarly, in addition to H3K36me2/me3-specific activity, RIOX1 preferentially demethylates H3K4me1/me3 residues [42]. Histone H3 lysine 79 methylation (H3K79me) is associated with a diverse range of cellular processes including telomeric silencing, cellular development, cell-cycle checkpoint, DNA repair, and transcription regulation [43]. However, only one H3K79-specific KMT is known, with no KDM for H3K79 demethylation reported to date. DOT1L is the sole enzyme that is responsible for all three forms of H3K79 methylation in humans [44]. In addition, DOT1L is unique because it is the only non-SET domain containing methyltransferase, which has been identified to date [18]. Methylation on Histone H4 lysine 20 (H4K20me) displays various biological processes depending on its methylated levels. H4K20me1 is associated with transcriptional activation, appearing in the most

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highly transcribed group of genes with other core modifications at active promoters [45]. H4K20me2 has distinct roles, such as marking points of replication origin and damage response in the DNA [46,47]. Conversely, H4K20me3 is associated with transcriptional repression at promoters and silencing of repetitive DNA and transposons [45,48]. H4K20me is catalyzed by three enzymes, with activities restricted to specific methylation states. KMT5A, the first identified H4K20 methyltransferase, is the only H4K20me1 enzyme [49]. H4K20me1 can be further di- and tri-methylated by KMT5B and KMT5C [50]. Similarly, several distinct demethylases are involved in the removal of specific H4K20me. PHF8 acts as a demethylase for H4K20me1 [51]. Intriguingly, as previously described, PHF8 is the KDM that has additional activities towards H3K9me1 and H3K9me2 [8]. In addition, LSD1n, an alternatively spliced form of KDM1A, demethylates H4K20me1 and H4K20me2 [52], while PHF2 displays demethylase activity on H4K20me3 [53]. 3. Neurodevelopmental Disorders Related with Histone Lysine Methylations 3.1. H3K4 Methylation 3.1.1. KMT2A and Wiedemann-Steiner Syndrome Mutations in KMT2A were reported to be associated with Wiedemann-Steiner syndrome (WDSTS; OMIM 605130), an extremely rare neurodevelopmental condition accompanied by microcephaly, short stature, autism-like phenotype, and aggression [54]. Interestingly, these abnormal brain functions were recapitulated in KMT2A heterozygous mutant mice, which displayed profound deficits in long-term contextual fear memory [55,56]. In particular, neuronal ablation of KMT2A in the postnatal forebrain and adult prefrontal cortex exhibited increased anxiety and robust cognitive deficits in mice. In the same study, the analyzing H3K4me3 level and the gene expression profiles in KMT2A-deficient cortical neurons revealed that the homeodomain transcription factor, MEIS2, was repressed in these mice. Moreover, MEIS2 knockdown in prefrontal cortex phenocopied memory defects elicited by the deletion of KMT2A [57], thus proposing a critical role of MEIS2 in the pathogenesis of WDSTS. 3.1.2. KMT2D and Kabuki Syndrome 1 The most well-studied neurodevelopmental disorder associated with dysregulated H3K4me is Kabuki syndrome 1 (KABUK1; OMIM 147920), which is a rare congenital syndrome characterized by a distinctive face (a reminiscent of the make-up of actors Kabuki, traditional Japanese music-drama) and mental retardation with additional features including autism, seizure, and microcephaly [58]. Heterozygous mutations in KMT2D were found in more than 50% of patients with KABUK1, with the majority of mutations resulting in the premature termination of the protein product. In addition, mutations in KDM6A, an H3K27me demethylase gene, were also reported to contribute to less than 10% of this syndrome, and this type is referred as Kabuki syndrome 2 (KABUK2; OMIM 300867) [59–62]. Recently, Bögershausen et al. identified two mutations in RAP1A/B, which encode the Ras family small GTPases, in patients with KABUK1 by whole exome sequencing [61]. The authors also demonstrated that mutant RAP1 morphant phenocopied KDM6A and KMT2D mutants in zebrafish, and that the MEK/ERK pathway signaling was perturbed in RAP1- and KMT2D-defective cells. Interestingly, these phenotypes were rescued by treatment with an MEK inhibitor. On the other hands, the reduction in neurogenesis and hippocampal memory defects exhibited in a KABUK1 mouse model were ameliorated by the treatment with a histone deacetylase (HDAC) inhibitor, AR-42 [63]. Furthermore, a ketogenic diet rescued hippocampal memory defects through the elevation of beta-hydroxybutyrate, an endogenous HDAC inhibitor, in the same mice model [64]. Taken together, these results potentially provide diverse therapeutic directions to treat, or at least mitigate, the symptoms of KABUK1.

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3.1.3. SETD1A and Schizophrenia Extensive exome sequencing from over 200 patients with schizophrenia (SCZD; OMIM 181500) revealed two de novo mutations in SETD1A, which likely cause malfunction of SETD1A activity [65]. Furthermore, a strong association between the loss-of-function mutation of SETD1A and SCZD was confirmed by analyzing the whole exome sequencing of over 4000 patients with SCZD [66]. Interestingly, a recent bioinformatic analysis demonstrated that in addition to mutations in the protein coding region, mutations in the regulatory elements of SETD1A also contributed to the etiology of SCZD. De novo synonymous mutations within frontal cortex-derived DNase I-hypersensitive sites were enriched in SCZD, and SETD1A was identified as the highest statistical significant gene [67]. 3.1.4. H3K4me Demethylases and Neurodevelopmental Disorders Given the intimate association between H3K4 methylation and neurodevelopment disorders, it is rational to assume that KDMs that are responsible for demethylation of H3K4me can be also mutated in neurodevelopmental disorders. Indeed, homozygous missense mutation in KDM5A has been reported in an individual with intellectual disability [68]. Furthermore, KDM5C, another H3K4 demethylase coding gene, has been recurrently mutated in patients with mental retardation, X-linked, syndromic, Claes-Jensen type (MRXSCJ; OMIM 300534) [68–70]. Intriguingly, KDM5C has been shown to be transcriptionally regulated by ARX, a homeobox transcription factor, which is frequently mutated in X-linked mental retardation and epilepsy [71–74]. Additionally, a missense mutation in amine oxidase domain of KDM1A has been reported in patients with mixed features of KABUK1 and KBG syndrome (KBGS; OMIM 148050), which are characterized by macrodontia, distinctive craniofacial findings, and intellectual disability [75]. It is noteworthy that KDM1A catalyzes the demethylation of mono- and di-methylated H3K4, while other KDMs can demethylate H3K4me1/2/3 [76]. 3.1.5. PHF21A and Potocki-Shaffer Syndrome Besides H3K4me writers and erasers, PHF21A, an unmethylated H3K4 reader, was associated with a neurodevelopmental disorder. PHF21A was translocated in patients with Potocki-Shaffer syndrome (PSS; OMIM 601224), characterized by multiple exostoses, parietal foramina, intellectual disability, and craniofacial anomalies [77–79]. This translocation commonly results in deletion of the PHD domain coding region of PHF21A, suggesting that dictation of unmethylated H3K4 is crucial for its functions. Accordingly, the deficiency of head development was observed in PHF21A morpholino-injected zebrafish, and this defect was rescued by injection of human PHF21A mRNA [78]. In addition, PHF21A, in combination with KDM1A, is a key component of the BHC complex, which is involved in the repression of neuron-specific genes [80]. Furthermore, SCN3A, a KDM1A target gene, was derepressed, and LSD1 occupancy at the SCN3A promoter was reduced in PHF21A-translocated lymphoblastoid cell lines [78], hence proposing the idea that interplay between KDM1A and PHF21A is indispensable for normal brain development. 3.2. H3K9 Methylation 3.2.1. EHMT1 and Kleefstra Syndrome Mutations in EHMT1, a gene encoding H3K9 methyltransferase, have been associated with Kleefstra syndrome (KS; OMIM 610253) which is characterized by intellectual disability, childhood hypotonia, and distinctive facial features [81,82]. Previously, this syndrome was known as the 9q Subtelomeric Deletion syndrome, in which minimal critical deleted region comprises EHMT1 [83]. In agreement with the role of EHMT1 on neurodevelopment in human, both Drosophila EHMT mutants and EHMT1 heterozygous knockout mice showed deficits in dendrite branching, learning, and memory [84,85]. Recent studies revealed the functions of EHMT1 in neurons, which may explain the phenotypes of patients and animal models of KS. A study measuring network and single cell activity in cortical cultures showed that EHMT1 is important for cortical neuronal network

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development [86]. Additionally, EHMT1 mediates homeostatic synaptic scaling, which stabilizes the activity of neural networks by balancing excitation and inhibition [87]. Interestingly, recent studies using exome sequencing revealed that the KS phenotypic spectrum was also linked to mutations in KMT2B and KMT2C [88,89], and these suggest that complicated epigenetic modules might underlie the pathogenesis of KS. 3.2.2. PHF8 and Siderius X-Linked Mental Retardation Syndrome Siderius X-linked mental retardation syndrome (MRXSSD; OMIM 300263) is an X-linked intellectual disability condition; patients display mental retardation, a long face and broad nasal tip, and cleft lip and palate [90,91]. MRXSSD has been associated with mutations in PHF8 [91–93]. Interestingly, PHF8 has a histone lysine demethylase activity towards three different methylated lysines on histones, H3K9me1/2 and H4K20me1 [94–96], and also functions as a trimethylated H3K4 reader [94]. Loss of a PHF8 homolog in Caenorhabditis elegans resulted in axon guidance defects via the alteration of Hedgehog-like signaling [97]. Furthermore, injection of zebrafish PHF8 morpholino caused brain and craniofacial development defects [96], thus suggested a critical role of histone methylation dynamics regulated by PHF8 in MRXSSD. However, surprisingly, a recent study showed that Phf8-deficient mice had no obvious developmental defects and cognitive impairment, while Phf8-deficient primary cells had reduced the proliferative potential [98]. The results in mice indicated that MRXSSD is not simply caused by a single PFH8 mutation, but rather by its combination with other genetic or environmental factors at the same time. The different phenotypes exhibited by some animal models and varying degrees of intellectual disability of human patients with MRXSSD can be attributed to the various targets and complex functions of PHF8. 3.3. H3K27 Methylation EZH2 and Weaver Syndrome Weaver syndrome (WVS; OMIM 277590) is an autosomal dominant disorder characterized by overgrowth and intellectual disability [99–101]. Exome sequencing studies identified EZH2 as a causative gene of WVS [102,103]. EZH2 interacts with EED to form PRC2, which is an H3K27me3 methyltransferase complex [104]. Interestingly, mutations in EED were found in individuals displaying symptoms similar to those of WVS [14,105], suggesting that the dysregulation of H3K27 methylation is responsible for these symptoms. Several studies have shown that EZH2 deficiencies in animal models induced abnormal neurogenesis in the cerebral cortex [106], cerebellum [107], and spinal cord [108] during embryonic development. Moreover, EZH2 is also implicated in adult hippocampal neurogenesis [109]. The alteration of neurogenesis induced by EZH2 deficiencies has been associated with various neurogenic processes, such as the reduction of neural progenitor cell proliferation [108–110], cell fate change [106,107,111–113], and neuronal migration [114–116]. These results suggest that EZH2-induced H3K27 methylation plays an important role in various processes of neurodevelopment, dysfunction of which might be closely related to intellectual disability in patients with WVS. 3.4. H3K36 Methylation 3.4.1. NSD1 Defects in Sotos Syndrome 1 and Beckwith-Wiedemann Syndrome Recent studies demonstrated that disrupted levels or patterns of H3K36 methylation can cause a range of human diseases, including neurodevelopmental disorders. Among them, Sotos syndrome 1 (SOTOS1; OMIM 117550) represents an important human model system for studying the neurodevelopmental outcome of epigenetic dysregulation, which is caused by mutations in NSD1 [117]. SOTOS1 is an autosomal dominant disorder characterized by pre- and postnatal overgrowth, facial

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dysmorphism, macrocephaly, and non-progressive neurological delay [118]. Interestingly, amplified genomic events of NSD1 resulted in the opposite phenotypic outcome of SOTOS1, so that duplication in NSD1 led to reversed clinical phenotypes of SOTOS1 with microcephaly, as well as delayed bone age, indicating the importance of proper NSD1 expression during brain development [119]. In addition, it was shown that neuroblastoma and glioma may occur in human in the absence of NSD1 function [120]. Although the MAPK/ERK pathway was mapped as a downstream signaling pathway of NSD1-related overgrowth of stature in SOTOS1 [121], until recently, the molecular mechanisms how dysregulated NSD1 affects the mental retardation in SOTOS1 patients remains elusive. To date, two Sotos-like overgrowth syndromes called as Sotos syndrome 2 (SOTOS2; OMIM 614753) and 3 (SOTOS3; OMIM 617169) have been reported, which are caused by mutations in the NFIX and APC2 genes, respectively [122,123]. Among the products of the two genes, APC2, a WNT signaling pathway regulator, has recently been suggested as a crucial target of NSD1, of which defects may cause the intellectual disability associated with SOTOS [123]. In the mouse model system, Apc2 deficiency caused impaired learning and memory abilities along with an abnormal head shape. In addition, Nsd1 knockdown downregulated endogenous Apc2 expression, and defective neuronal phenotypes caused by the knockdown were rescued by the forced expression of Apc2, suggesting that APC2 may be a critical downstream gene of NSD1 in human neuronal cells. Beckwith-Wiedemann syndrome (BWS; OMIM 130650) is another distinct overgrowth disorder with a broad clinical spectrum including hypoglycemia, ear creases/pits, cleft palate, and predisposition to embryonal tumors [124]. Martinez-y-Martinez et al. documented that mental retardation was observed in 6 of the 39 BWS cases [125]. It is well known that a major cause of BWS is the dysregulation of imprinted growth regulatory genes on chromosome 11p15 [126]. Interestingly, mutations in the NSD1 gene have been identified in 2 patients among 52 individuals clinically diagnosed with BWS, which suggests the involvement of NSD1 in imprinting of the 11p15 region [127]. 3.4.2. NSD2 and Wolf-Hirshhorn Syndrome NSD2 is one of the major genes associated with Wolf-Hirshhorn syndrome (WHS; OMIM 194190), of which key features include severe growth and mental retardation, microcephaly, “Greek helmet” facies, and closure defects [128]. Like patients with WHS, mice with Nsd2 gene deletions were growth-retarded, showed midline, craniofacial, and ocular anomalies [129]. However, these mice did not show any learning deficits [129]. Although the downstream effectors of NSD2, such as RUNX2 and p300, which are known to play a role in bone development [130], have been identified, the mechanism by which NSD2 deficiency causes neurological disorders in patients with WHS is still unknown. 3.5. H4K20 Methylation Siderius X-Linked Syndromic Mental Retardation and Meier-Gorlin Syndrome 1 Thus far, two developmental diseases associated with dysregulated H4K20 methylation have been reported in human. As described above, one is MRXSSD (OMIM 300263) caused by mutations in PHF8, which encodes an eraser of H3K9 and H4K20 methylation. The other is Meier-Gorlin syndrome 1 (MGORS1; OMIM 224690) caused by homozygous or compound heterozygous mutation in the ORC1 gene [131], which encodes a specific reader of H4K20me2 [46]. MGORS1 is a rare disorder characterized by severe intrauterine, postnatal growth retardation, and microcephaly [132]. Interestingly, however, despite the presence of microcephaly, intellects of patients with MGORS1 are usually normal [133]. 4. Perspectives As reviewed above, the pathogenesis of various neurodevelopmental disorders is closely associated with alterations in histone methylation status, which, in many cases, can be primarily attributed to loss-of-function mutations in related factors. Given that histone methylation status

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is meticulously regulated by the balance between two opposing enzymes (i.e., KMTs and KDMs), pharmaceutical inhibition of specific targets counteracting the loss-of-function mutations responsible for diseases can be a possible therapeutic option. Interestingly, a subset of currently available psychotherapeutic drugs, such as the atypical antipsychotic Clozapine, the mood-stabilizer Valproate, and the antidepressant Phenelzine are known to interfere with histone methylation in the brain [134], although the relative contribution of this interference to their psychotherapeutic effects remains to be elucidated. In principle, an estimated 100 lysine and arginine residue-specific histone methyltransferases and demethylases [135] can be reasonable therapeutic targets, since they are considered more specific than HDACs [134]. Of note, histone methylation has been the most flourishing area of epigenetics research recently, and in line with this, huge efforts have been made to develop several potential therapeutic molecules, which specifically regulate histone methyltransferases and methylation reader proteins, particularly for cancer treatment [136]. For example, selective inhibitors, such as EPZ005687, GSK126, and EI1, which target EZH2 of PRC2, were recently reported by three independent groups to inhibit proliferation of B-cell lymphomas harboring EZH2-activating mutations [137–139]. In addition, tranylcypromine derivatives and polyaminoguanidine derivatives were designed and characterized to inhibit histone demethylases with potential anti-cancer activity [136]. Several epigenetic compounds, such as ORY-1001 and GSK2879552, are currently undergoing clinical trials for cancer treatment. If they meet the required biosafety standards, they could potentially be strong candidates for treating neurodevelopmental disorders, by correcting the impaired histone methylation status. Moreover, a microRNA-based gene silencing strategy targeting a specific histone methyltransferase or demethylase can be an alternative therapeutic option to consider in this regard. Indeed, several studies have reported the important roles of miRNA in histone methylation and following transcriptional gene silencing in various model systems [140–142]. Although further research is warranted, it will be interesting to establish whether these epigenetic compounds and/or microRNA-based specific gene silencing approaches have obvious therapeutic benefits for the patients with the neurodevelopmental disorders outlined in this review. Acknowledgments: This work was supported by the DGIST R&D and MIREBraiN program, Basic Science Research Program through the ministry of science, ICT & future planning of Korea (17-BD-0402, 17-BT-02, and 17-01-HRSS-02); the Development of Platform Technology for Innovative Medical Measurements Program from the Korea Research Institute of Standards and Science (KRISS-2017-GP2017-0020) (Sung Bae Lee); the Basic Science Research Program of the National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology (NRF-2014R1A1A2056768 and NRF-2017R1A2B4004241 Kyoung Sang Cho), and NRF-2014R1A1A3051462) (Im-Soon Lee); the Korea Health Technology Research & Development Project, Ministry of Health & Welfare, Republic of Korea (HI12C1472) (Kyoung Sang Cho); and KRIBB initiative program (Jeong-Hoon Kim). Author Contributions: Sung Bae Lee and Kyoung Sang Cho designed the review; and Jeong-Hoon Kim, Jang Ho Lee, Im-Soon Lee, Sung Bae Lee and Kyoung Sang Cho wrote the manuscript. Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations APC2 ARX ASH1L BHC complex BWS DOT1L EED EHMT1 EHMT2 ERK ESC

Adenomatosis polyposis coli 2 Aristaless related homeobox ASH1 like histone lysine methyltransferase BRAF35/histone deacetylase complex Beckwith-Wiedemann syndrome DOT1 like histone lysine methyltransferase Embryonic ectoderm development Euchromatic histone lysine methyltransferase 1 Euchromatic histone lysine methyltransferase 2 Extracellular signal-regulated kinase Embryonic stem cells

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EZH1 EZH2 FAD H3K4 H3K4me H3K9 H3K9me H3K27 H3K27me H3K36 H3K36me H3K79 H3K79me H3R2 H3R8 H3R17 H3R26 H4K20 H4K20me H4R3 HDAC HP1 JHDM JmjC KABUK1 KABUK2 KBGS KS LSD1n KDM KMT MAPK MEIS2 MEK MGORS1 MRXSCJ MRXSSD NFIX NSD1 NSD2 NSD3 ORC1 PHF2 PHF21A PHF8 PRC1 PRC2 PRDM PSS

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Enhancer of zeste 1 polycomb repressive complex 2 subunit Enhancer of zeste 2 polycomb repressive complex 2 subunit Flavin adenosine dinucleotide Histone H3 lysine 4 Methylation on histone H3 lysine 4 Histone H3 lysine 9 Methylation on histone H3 lysine 9 Histone H3 lysine 27 Methylation on histone H3 lysine 27 Histone H3 lysine 36 Methylation on histone H3 lysine 36 Histone H3 lysine 79 Methylation on histone H3 lysine 79 Histone H3 arginine 2 Histone H3 arginine 8 Histone H3 arginine 17 Histone H3 arginine 26 Histone H4 lysine 20 Methylation on histone H4 lysine 20 Histone H4 arginine 3 Histone deacetylase Heterochromatin protein 1 JmjC-domain containing histone demethylases Jumonji C Kabuki syndrome 1 Kabuki syndrome 2 KBG syndrome Kleefstra syndrome Lysine-specific demethylase 1 variant Lysine demethylase Lysine methyl transferase Mitogen-activated protein kinase Myeloid ecotropic viral integration site 1 homolog 2 Mitogen-activated protein kinase kinase Meier-Gorlin syndrome 1 Mental retardation, X-linked, syndromic, Claes-Jensen type Siderius X-linked mental retardation syndrome Nuclear factor I X Nuclear receptor-binding SET domain protein 1 Nuclear receptor-binding SET domain protein 2 Nuclear receptor-binding SET domain protein 3 Origin recognition complex subunit 1 PHD finger protein 2 PHD finger protein 21A PHD finger protein 8 Polycomb repressive complex 1 Polycomb repressive complex 2 PR/SET domain family Potocki-Shaffer syndrome

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RAP1A/B RIOX1 RUNX2 SCZD SCN3A SETD1A SETD1B SETD2 SETD3 SETDB1 SETMAR SMYD2 SOTOS1 SOTOS2 SOTOS3 SUV39H1 SUV39H2 UTY WDSTS WHS WVS

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RAS-related protein 1A/B Ribosomal oxygenase 1 Runt related transcription factor 2 Schizophrenia Sodium voltage-gated channel alpha subunit 3 SET domain containing 1A SET domain containing 1B SET domain containing 2 SET domain containing 3 SET domain bifurcated 1 SET domain and mariner transposase fusion gene SET and MYND domain containing 2 Sotos syndrome 1 Sotos syndrome 2 Sotos syndrome 3 Suppressor of variegation 3-9 homolog 1 Suppressor of variegation 3-9 homolog 2 Ubiquitously transcribed tetratricopeptide repeat containing, Y-linked Wiedemann-Steiner syndrome Wolf-Hirshhorn syndrome Weaver syndrome

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